Abstract/Project Summary This application describes the research plan and program of study leading to a PhD as part of a combined MD- PhD Program at the University of Nebraska Medical Center. The central goal of the research plan is to identify how aberrant brain dynamics related to HIV infection differ in those who use cannabis. People living with HIV (PLWH) are at a significant risk for developing neurologic comorbidities such as HIV-associated neurocognitive disorder (HAND). Additionally, many PLWH are chronic cannabis users, and such use itself is thought to alter long-term brain function, and potentially modulate the neural changes associated with HIV. Advanced neuro- imaging studies using magnetoencephalography (MEG) have identified specific changes in the neural dynamics related to HIV infection and HAND, however, it is unknown whether these dynamics differ in those who chronically use cannabis. Thus, the proposed line of research aims to address this knowledge gap by using MEG imaging in a group of PLWH who are chronic cannabis users and comparing them to PLWH who are non-users, chronic cannabis users without HIV, and a non-user uninfected control group. All participants will undergo neuro- psychological testing to relate cognitive performance to neural measures. Using MEG, we will identify the neuro- physiological dynamics altered by HIV and cannabis use by quantifying task-based and spontaneous neural oscillatory activity during three cognitive paradigms, which are known to elicit neural activity related to visual- spatial processing, selective attention, and verbal working memory. Each of these tasks have been shown to elicit differences in neural oscillatory activity between PLWH and uninfected controls. MEG data will be imaged using an advanced beamforming approach to generate dynamic functional maps, and groups will be compared using ANOVAs, with between-subjects factors of HIV infection and chronic cannabis use. This will not only allow for the identification of neural changes associated with HIV and cannabis use independently, but also determine the interaction between HIV infection and cannabis use. Additionally, alcohol use will be examined as a factor of interest to determine the effect of increasing alcohol use within our sample. Our specific aims are: (1) To quantify the neural dynamics associated with chronic cannabis use and HIV-infection in regards to activity serving spatial processing, attention, and working memory, and examine how HIV-related aberrations differ in cannabis users by studying cannabis users and nonusers with and without HIV-infection., and (2) to determine the interaction between chronic cannabis and alcohol use in regards to brain and cognitive function in PLWH. In summary, we will utilize MEG, advanced source reconstruction methods, neural oscillatory analyses, and neuropsychological testing to delineate the neurophysiological relationship between chronic cannabis use and HIV infection. The program of study is designed to support this research plan by incorporating rigorous training by established mentors who are leaders in the fields of HIV and drug use, with the primary goal of developing and expanding the research and clinical skills of the applicant to produce a successful physician-scientist.